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<ul><li><p>Essentials for physicians and health care professionals ordering and interpreting urinary </p><p>screens for drugs of abuse. </p><p>Dr. Edward Randell </p></li><li><p>Disclosure of Potential for Conflict of Interest </p><p>FINANCIAL DISCLOSURE Grants/Research Support: CIHR and others. Speakers Bureau/Honoraria: None Consulting Fees: None Other: Employee of Memorial University </p></li><li><p>Learning Objectives </p><p> Describe why urine is the preferred sample for drug of abuse screening </p><p> Describe common interfering substances Identify factors to consider when interpreting </p><p>positive and negative drug screens Describe the strengths and limitations of </p><p>common techniques used for urine drug screening </p></li><li><p>Why are UDS important to clinical practice? </p><p> Can identify more non-adherent patients than monitoring behavior and self-reporting alone </p><p> Identify new or recurrent drug misuse Support clinical decisions Assist diagnosis Deterrent and provide objective evidence of </p><p>abstinence in high risk patients </p></li><li><p>Why is interpreting UDS correctly important? </p><p> UDS screen interpretation carries significant potential for harm if done incorrectly </p><p> False accusations of drug abuse or diversion based on misinterpretation of UDS results carry potential medicolegal consequences. </p><p>Health care professionals who effectively employ UDS have a good understanding of the pharmacology of commonly encountered drugs and work closely with lab professionals when ordering and interpreting these tests </p></li><li><p>Drug Screens </p><p>Common Drug of Abuse </p><p>Amphetamines and Methamphetamine </p><p>Opiates </p><p>Benzodiazepines </p><p>Cocaine </p><p>Barbiturates </p><p>Methadone </p><p>Phencyclidine </p><p>Marijuana </p><p>Oxycodone </p></li><li><p>Introduction </p><p>Check out discuss of similar case at: http://paindr.com/two-puffs-too-bad-demystifying-marijuana-urine-testing/ </p><p>A 40 years old female receiving Oxycodone, presents to a pain clinic for routine follow-up visit. A random urine drug screen is done by immunoassay and she tests positive for Marijuana (cannabinoids positive). When asked, she admits I only smoked two puffs five days ago. Fact or Myth? </p></li><li><p>Quiz: 7 UDS questions What is detected in the urine following: </p><p>1. Acetaminophen/Codeine administration 2. Morphine administration 3. Heroine use 4. Poppy seed consumption 5. 2nd hand exposure to Marijuana smoke </p><p>6. Explain a negative drug screen result for a patient on chronic opioid therapy 7. On receiving a negative result on an opiate screen for a patient you prescribed hydromorphone you would </p></li><li><p> To determine level of UDS interpretative knowledge of physicians who use UDS to monitor adherence on chronic opioid therapy </p><p> 7 question survey given to 114 physicians 77 who use UDS regularly 37 who didnt </p><p>Reisfield, G. M., Bertholf, R., Barkin, R. L., Webb, F., &amp; Wilson, G. (2006). Urine drug test interpretation: what do physicians know?. Journal of opioid management, 3(2), 80-86. </p></li><li><p>Reisfield, G. M., Bertholf, R., Barkin, R. L., Webb, F., &amp; Wilson, G. (2006). Urine drug test interpretation: what do physicians know?. Journal of opioid management, 3(2), 80-86. </p></li><li><p>Reisfield, G. M., Bertholf, R., Barkin, R. L., Webb, F., &amp; Wilson, G. (2006). Urine drug test interpretation: what do physicians know?. Journal of opioid management, 3(2), 80-86. </p></li><li><p> 99 internal medicine residents Compared personal confidence with </p><p>interpreting drug screens vs. measured performance. </p><p>Starrels, J. L., Fox, A. D., Kunins, H. V., &amp; Cunningham, C. O. (2012). They dont know what they dont know: Internal medicine residents knowledge and confidence in urine drug test interpretation for patients with chronic pain. Journal of general internal medicine, 27(11), 1521-1527. </p></li><li><p>Starrels, J. L., Fox, A. D., Kunins, H. V., &amp; Cunningham, C. O. (2012). They dont know what they dont know: Internal medicine residents knowledge and confidence in urine drug test interpretation for patients with chronic pain. Journal of general internal medicine, 27(11), 1521-1527. </p><p>There was no significant differences in interpreting drug screens among medical residents stating confidence in their ability versus those acknowledging lack of confidence. </p></li><li><p>Brief History of Drug screening 1950s blood tox screens </p><p>1960s TLC 1970s IA and </p><p>POC testing </p><p>1980s IA + GC-MS </p><p>21st Century LC-MS/MS </p><p>1950s Emergency Rooms and Death </p><p>investigations </p><p>1970s: Addiction treatment &amp; criminal justice </p><p>1970s Methadone maintenance/Opioid </p><p>Treatment/Military Workplace/Industry/Govt. </p><p>Highway safety </p></li><li><p>The Technology used for UDS </p></li><li><p>How are DOAs screened? </p><p>Immunoassay GC-MS (Gas Chromatography coupled to Mass </p><p>Spectrometry) LC-MS (Liquid Chromatography coupled to Mass </p><p>Spectrometry) </p></li><li><p>Actually the following list is more accurate Method Common Abbreviation </p><p>Cloned enzyme donor immunoassay CDIA </p><p>Enzyme-linked immunosorbent assay ELISA </p><p>Enzyme-multiplied immunoassay technique EMIT </p><p>Fluorescence polarization immunoassay FPIA </p><p>Radioimmunoassay RIA </p><p>Point of care testing methods POCT </p><p>Gas Chromatography Mass Spectrometry GC-MS </p><p>Liquid Chromatography Ultraviolet Detection HPLC-UV </p><p>Liquid Chromatography High Resolution Mass spectrometry LC-hrMS </p><p>Liquid Chromatography tandem mass spectrometry LC-MS/MS </p><p>Liquid Chromatography time-of-flight mass spectrometry LC-TOF </p><p>Thin Layer Chromatography TLC </p></li><li><p>Immunoassay Urine Drug Screens (UDS) Uses antibodies specific for drug or common </p><p>metabolite target Detection of a drug depends on antibody </p><p>specificity, cut-off, and drug concentration. Immunoassay-based Lab Methods </p><p> Automated on laboratory analyzers </p><p> Immunoassay-based POCT devices Presence of band indicates a positive result </p></li><li><p>GC-MS </p><p>Barbosa, S. S., Leal, F. D., Padilha, M. C., Silva, R. S., Pereira, H. M. G., Aquino Neto, F. R., &amp; Silva Jnior, A. I. D. (2012). Specificity and selectivity improvement in doping analysis using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry. Qumica Nova, 35(5), 982-987. </p></li><li><p>LC-MS/MS </p><p>20 Eichhorst, J. C., Etter, M. L., Rousseaux, N., &amp; Lehotay, D. C. (2009). Drugs of abuse testing by tandem mass spectrometry: a rapid, simple method to replace immunoassays. Clinical biochemistry, 42(15), 1531-1542. </p></li><li><p>UDS techniques are targeted or untargeted </p><p>Targeted drug screens - identify specific drugs to screen excluding most others. </p><p> Most common: Immunoassay &amp; LC-MS/MS All UDS commonly used in NL are targeted. Untargeted drug screens are broad drug </p><p>screens without exclusion. GC-MS and LC-hrMS methods are untargeted. </p></li><li><p>Comparison of UDS techniques Screening Screening/Confirmatory </p><p>Analysis Immunoassay GC-MS or LC-MS/MS </p><p>Ability to detect drug class (Sensitivity) </p><p>Low to nil for synthetic opioids but fair for others </p><p>High </p><p>Ability to discriminate drug from similar compounds (Specificity) </p><p>Variable-false positives and false negatives </p><p>High </p><p>Use Qualitative screen Quantitative confirmation </p><p>Cost Variable Variable </p><p>TAT rapid Many days </p><p>Application Works best for screening drug-free population; may be less useful in pain-management. </p><p>Definitive &amp; Legally defensible </p><p>Interpretation Complex Complex </p></li><li><p>Why urine? </p></li><li><p>Why is urine the most used sample? </p><p> Easy to obtain Minimal preparation Most drugs of interest &amp; their metabolites </p><p>concentrate in urine Good sensitivity and specificity for recent use Wider window of detection compared to blood </p></li><li><p>Positivity in urine indicates exposure ...But </p><p> Does not correlate with clinical status Can miss very recent exposure Positivity means different things depending on </p><p>the screening method used. </p></li><li><p>Interpreting urine drug screens </p><p>Urine Drug Test Positive Negative </p><p>Patie</p><p>nt re</p><p>port</p><p>s ta</p><p>king</p><p> the </p><p>drug</p><p>Yes </p><p>True Positive 1. Patient is taking the drug as </p><p>reported. 2. Test detects the substance </p><p>reported </p><p>False Negative 1. Patient may be mistaken about </p><p>taking the drug. 2. Last dose too low or too long ago to </p><p>be detected. </p><p>No </p><p>False Positive 1. Interfering substance 2. Unreported self-</p><p>administration of a cross-reacting substance </p><p>True Negative 1. Patient is not taking the drug as </p><p>reported. 2. UDS does not detect the substance. </p></li><li><p>UDS Interpretation </p><p>Factors Affecting UDS interpretation </p><p>Time since ingestion </p><p>Duration of use </p><p>Administration Route Urine volume </p><p>Hydration Status </p><p>Amount of drug ingested </p><p>Diet </p><p>Urine pH </p><p>Concurrent Medications </p><p>Urinary frequency </p><p>Testing Method </p><p>Dosage Intervals </p><p>Disease State Body Weight </p><p>Individual metabolism </p></li><li><p>Interpreting UDS </p><p> Unexpected interferences Target Compounds Cut-offs Windows of Detection Importance of considering drug metabolism </p></li><li><p>Common Immunoassay Interferences Target Drugs Interfering Drugs </p><p>Amphetamines Diet Pills, Vicks inhaler (US), Trazodone, Aripiprazole, Promethazine and Phentermine </p><p>Marijuana Efavirenz (Antiretroviral), baby shampoo and soap, pantoprazole and possibly other proton pump inhibitors </p><p>Hydromorphone Hydrocodone </p><p>Methadone Quetiapine </p><p>Fentanyl Trazodone </p><p>TCAs Quetiapine </p><p>Opiates/Morphine Poppy Seeds, Quinolone antibiotics </p><p>Benzodiazepines Sertraline </p><p>PCP Venlafaxine </p></li><li><p>Agents that can cause positive results on amphetamine immunoassay. </p><p>Moeller, K. E., Lee, K. C., &amp; Kissack, J. C. (2008, January). Urine drug screening: practical guide for clinicians. In Mayo Clinic Proceedings (Vol. 83, No. 1, pp. 66-76). Elsevier </p><p>Cross-reactivity is a common problem for UDS relying on immunoassay technique. </p></li><li><p>Moeller K E et al. Mayo Clin Proc. 2008;83:66-76 </p></li><li><p>Different methods have different targets </p><p>Drug/Class Immunoassay Screen Mass Spectrometry Benzodiazepines Oxazepam Specific Drugs: Diazepam, </p><p>Oxazepam, Loraxepam, Temazepam, Alprazolam, Clonazepam </p><p>Opiates Morphine Specific Drugs: Morphine, Codeine, Oxycodone, Fentanyl, Hydromorphone. </p><p>Cocaine Cocaine Metabolite Cocaine and Benzoeconine Marijuana THC metabolite THC and THC-COOH Amphetamine &amp; Methamphetamine </p><p>Amphetamine &amp; Methamphetamine </p><p>Specific Drugs: Amphetamine, MDA, MDMA, metamphetamine </p><p>Some Mass Spectrometry methods are non-targeted meaning that they detect everything and both suspected and unsuspected can be explored. </p></li><li><p>Moeller K E et al. Mayo Clin Proc. 2008;83:66-76 </p><p>For both Morphine and Codeine </p><p>Different methods have different cutoffs. </p><p>Cutoffs determine the drug concentration at which a positive result is reported. This is not the same as a detection limit. </p></li><li><p>For how will a UDS remain positive? </p><p>Most- 1 to 3 days Some (marijuana, diazepam, ketamine, PCP) may </p><p>be detected for a week or more Depends of urine concentration of drug and assay </p><p>cutoff </p></li><li><p>Excretion pattern of Cocaine </p><p>0</p><p>2000</p><p>4000</p><p>6000</p><p>8000</p><p>10000</p><p>12000</p><p>0 10 20 30 40 50 60</p><p>Cocaine (base) 42 mg smoked BenzoyleconineEcgonine Methyl esterCocaine</p><p>Cone, E. J., Sampson-Cone, A. H., Darwin, W. D., Huestis, M. A., &amp; Oyler, J. M. (2003). Urine testing for cocaine abuse: metabolic and excretion patterns following different routes of administration and methods for detection of false-negative results. Journal of analytical toxicology, 27(7), 386-401 </p><p>Detected by immunoassay (300 g/L) </p></li><li><p>Marijuana (Heavy use) (Moderate use) </p><p>Benzodiazepines (Long acting) </p><p>Barbiturate (long acting) </p><p>Window of detection in urine </p><p>2 days 4 days 6 days 1 week 2 weeks </p><p> (Short acting) </p><p>(Short) </p><p>(Single use) </p><p>Amphetamine &amp; Metamphetamine </p><p>Alcohol and Phencyclidine </p><p>Moeller K E et al. Mayo Clin Proc. 2008;83:66-76 </p><p>Cocaine </p></li><li><p>Meperidine </p><p>Window of detection in urine </p><p>1 days 2 days 3 days </p><p>Methadone </p><p>Oxycodone </p><p>Morphine from Heroine </p><p>Morphine </p><p>Moeller K E et al. Mayo Clin Proc. 2008;83:66-76 </p><p>Codeine </p><p>4 days </p><p>Up to 6 days if metabolite tested </p><p>Heroine only a few hours </p><p>Often missed </p><p>Often missed </p></li><li><p>Window of detection based on sample type. </p><p>Minutes Hours Days Weeks Months Years </p><p>Blood </p><p>Saliva </p><p>Urine </p><p>Sweat </p><p>Hair </p></li><li><p>Drug Metabolism must be considered </p><p>Benzodiazepine assays are prone to false negatives. </p></li><li><p>Drug metabolism must be considered. </p></li><li><p>Implication of cutoffs and cross-reactivity to immunoassay. </p><p>Smith, M. L., Shimomura, E. T., Summers, J., Paul, B. D., Nichols, D., Shippee, R., ... &amp; Cone, E. J. (2000). Detection times and analytical performance of commercial urine opiate immunoassays following heroin administration. Journal of Analytical Toxicology, 24(7), 522-529. </p></li><li><p>Drugs detected by opioid screens using mass spectrometry </p><p>Drug Mass Spectrometry </p><p>Heroine 6 monoacetyl morphine Morphine </p><p>Codeine Codeine Morphine Hydrocodone </p><p>Oxycodone Oxycodone Oxymorphone Hydrocodone </p><p>Poppy Seeds Morphine </p><p>Hydrocodone Hydrocodone Hydromorphone </p><p>Fentanyl Fentanyl Norfentanyl </p></li><li><p>Most drug screens identify opiates not opioids </p><p>Opioid Chemicals that work by </p><p>binding opioid receptors Opiates + semisynthetic Heroin, hydrocodone, </p><p>Hydromorphone, oxycodone, Fentanyl, Meperidine, </p><p>Opiate Natural alkaloids derived </p><p>from opium poppy Codeine and Morphine </p><p>Many Opioids and Benzodiazepines are missed by routine immunoassay UDS. </p></li><li><p>Interpretation </p><p>Negative for prescribed medication </p><p>Diversion </p><p>Patient run out of medication </p><p>Patient not taking full amount </p><p>Sample tampering </p><p>Immunoassay testing (false negative) </p></li><li><p>Interpretation </p><p>Positive for un-prescribed medication </p><p>Drug Abuse </p><p>Testing error: False Positive (poppy seeds) </p><p>Laboratory error: testing or clerical </p><p>Variability: within and between patients </p><p>Immunoassay testing </p></li><li><p>Open communication with lab is required </p><p>1. The clinical value of UDS depends on the level of interaction between the ordering physician and testing lab. </p><p>2. Appropriate lab use requires consideration of: 1. The purpose of the UDS 2. Why, who, and when the test is done 3. The limits of the lab results 4. What is meant in lab reporting terminology 5. The significance of screening cutoffs </p></li><li><p>How people beat drug tests </p><p>1. Substitution with synthetic urine or purchased drug free urine </p><p>2. Flush out with commercially available product 3. Adulteration by adding reactive or masking </p><p>substance to the urine 1. Visine eye drops, Salt, Oxidizing agents, Potassium </p><p>Nitrite, glutaraldehyde. </p></li><li><p>Finding Cheats: A few simple tests </p><p>Sample Temperature 90 to 100 for first 4 minutes </p><p>pH Should be 4.5 to 8 </p><p>Creatinine Should be &gt;3 mmol/L </p><p>Nitrite Negative </p></li><li><p>Conclusions </p></li><li><p>Quiz: 7 UDS questions What is detected in the urine following: </p><p>1. Acetaminophen/Codeine administration 2. Morphine administration 3. Heroine Use 4. Poppy seed consumption 5. 2nd hand exposure to Marijuana smoke </p><p>6. Explain a negative drug screen result for a patient on chronic opioid therapy. 7. On receiving a negative result on an opiate screen for a patient you prescribed hydromorphone you would </p><p>(Codeine &amp; Morphine) </p><p>(Morphine) </p><p>(6 monoaceylmorphine &amp; Morphine) </p><p>(Morphine) </p><p>(Nothing) </p><p>(Which opioid? Screen may not measure.) </p><p>(Most screens do not measure hydromorphone. Request confirmatory procedure) </p></li><li><p>Effective UDS use depends on: </p><p>Good relationship with Lab </p><p>Know which test lab is using </p><p>Insure screening results are </p><p>confirmed before serious action </p><p>Choose testing strategy based on purpose of testing </p><p>Know recent medication history </p><p>Insure proper collection and </p><p>labelling </p></li><li><p>References Dowell, D., Haegerich, T. M., &amp; Chou, R. (2016). CDC guideline for prescribing opioids for chronic painUnited </p><p>States, 2016. JAMA, 315(15), 1624-1645. Moeller, K. E., Lee, K. C., &amp; Kissack, J. C...</p></li></ul>